Is GAN p.Pro288Ala (c.862C>G) pathogenic?

GAN p.Pro288Ala (c.862C>G) is classified Uncertain significance in GAN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1408); Very rare (popmax 0.00136%, nfe); Associated with giant axonal neuropathy 1.

What condition is associated with GAN p.Pro288Ala (c.862C>G)?

GAN p.Pro288Ala (c.862C>G) is associated with giant axonal neuropathy 1 (ClinVar).

How common is GAN p.Pro288Ala (c.862C>G) in the general population?

GAN p.Pro288Ala (c.862C>G) is very rare (popmax 0.00136%, nfe) (gnomAD).

How is Giant axonal neuropathy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about GAN p.Pro288Ala (c.862C>G)?

AlphaMissense predicts likely benign (score 0.1408) — an in-silico prediction, not a clinical call.

GAN p.Pro288Ala

c.862C>G · rs1249160013 · VCV665088

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1408 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

giant axonal neuropathy 1

Computational evidence

Protein change
AlphaMissense	0.1408	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 62 kb · p 1.3e-08 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,366 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,613,294 alleles · very rare exomes 13/1,461,116 · genomes 3/152,178 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GAN
Protein: p.Pro288Ala
Coding: c.862C>G
MANE Select: NM_022041
dbSNP: rs1249160013
Type: single nucleotide variant
Location: chr16:81357820 (GRCh38)
Gene constraint: LOEUF 0.842 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.93 · 2 PDB

Full GAN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

giant axonal neuropathy 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Giant axonal neuropathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

GAN p.Pro288fs Pathogenic ★ same residue
GAN p.Pro288Arg Uncertain significance ★ ⚠ same residue
GAN p.Pro288Leu Uncertain significance ★ ⚠ same residue
GAN c.1502+1G>T Pathogenic/Likely pathogenic ★★ same condition
GAN c.851+1G>A Pathogenic/Likely pathogenic ★★ same condition
GAN p.Arg545His Pathogenic/Likely pathogenic ★★ same condition
GAN p.Gln103Ter Pathogenic ★★ same condition
GAN p.Glu486Lys Pathogenic/Likely pathogenic ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gan-p-pro288ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown